The general method for preparing ampicillin by acylating 6-aminopenicillanic acid (which in the following is abbreviated as 6-APA) with D(-)-.alpha.-phenylglycylchloride.HCl according to the overall equation ##STR1## has long been known in the art.
A commonly used procedure for carrying out the above acylation of 6-APA, comprises silylating 6-APA with a silylating agent such as an organo-silyl chloride in the presence of an organic base such as triethylamine and a solvent, then coupling the silylated 6-APA with the phenylglycylchloride.HCl in the presence of a weak base and a solvent, hydrolyzing the resulting silylated ampicillin to remove the protective silyl group therefrom and isolating the formed ampicillin from the reaction mixture.
The key step in the conversion of 6-APA into ampicillin is the amide bond forming reaction in the presence of a weak base. The latter has to serve as an acid acceptor for the hydrochloric acid generated in this step, yet should not adversely affect the condensation reaction between the acyl chloride and the amino group of the silylated 6-APA. N,N-dimethylaniline has been found to be a suitable acid acceptor providing good yields of ampicillin on an industrial scale production. Unfortunately dimethylaniline is a cancer suspect agent and residual amounts of dimethylaniline or its hydrochloride in the final ampicillin product may provide a serious health hazard.